3-Hydroxy-2-(trialkylsilyl)phenyl Triflate: A Benzyne Precursor Triggered via 1,3-C-sp2-to-O Silyl Migration

Article abstract of DOI:10.1021/acs.orglett.7b03160

3-Hydroxy-2-(trialkylsilyl)phenyl triflates are presented as new versatile hydroxyaryne precursors. These are base-activated aryne precursors induced via a C-sp²-to-O 1,3-Brook rearrangement. The reaction of various arynophiles and 3-trialkylsiloxybenzyne generated from 3-hydroxy-2-(trialkylsilyl)phenyl triflate efficiently afforded highly regioselective phenol derivatives. Furthermore, through crossover experiments, the intramolecular mechanism of silyl migration was demonstrated.

Full text of DOI:10.1021/acs.orglett.7b03160

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX-XXX
3‑Hydroxy-2-(trialkylsilyl)phenyl Triflate: A Benzyne Precursor
Triggered via 1,3-C-sp2‑to‑O Silyl Migration
Yong-Ju Kwon,†,∥ Young-Kyo Jeon,†,∥ Ha-Bin Sim,† In-Young Oh,† Inji Shin,‡,§ and Won-Suk Kim*,†
†Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760, Korea
‡Department of Drug Discovery Research, Korea Research Institute of Chemical Technology, Daejeon 34602, Korea
§Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon 34101, Korea
S
* Supporting Information
ABSTRACT: 3-Hydroxy-2-(trialkylsilyl)phenyl triflates are
presented as new versatile hydroxyaryne precursors. These
are base-activated aryne precursors induced via a C-sp2-to-O
1,3-Brook rearrangement. The reaction of various arynophiles
and 3-trialkylsiloxybenzyne generated from 3-hydroxy-2-
(trialkylsilyl)phenyl triflate efficiently afforded highly regiose-
lective phenol derivatives. Furthermore, through crossover experiments, the intramolecular mechanism of silyl migration was
demonstrated.
n the Brook rearrangement, initially introduced by Brook et
al.,1 a negative charge moves from an oxygen to carbon
through the transfer of a silyl group. The mechanism of the Brook
rearrangement has been extensively studied and is now known to
be a reversible process proceeding intramolecularly via a
hypervalent silicon intermediate (Scheme 1a).2 This rearrange-
silylphenol through a retro-Brook rearrangement process.6 This
could be due to the relative stability of the resultant phenolate
compared to that of the aryl carbanion derived from the starting
aryl halide.8 Furthermore, treatment of the in situ generated
phenolate with triflic anhydride can furnish o-silylaryl triflates,
which are useful benzyne precursors developed by Kobayashi et
al.6b Currently, o-silylaryl triflates are the most widely employed
benzyne precursors because of their efficiency and the mild
conditions necessary to generate benzyne, which are triggered by
a fluoride anion at room temperature or higher.7 For example, Li
and co-workers reported a new domino aryne precursor that can
be used for the preparation of 1,2,3-trisubstituted benzenes.7e In
2016, Hosoya et al. demonstrated the synthesis of 3-aminoaryne
precursors employing aryne relay chemistry and utilized them for
the synthesis of various anilines.7i Considering the recent
advances in benzyne chemistry, we hypothesized that hydroxy-
substituted arynes could be used as potential intermediates in the
synthesis of various phenol derivatives. In addition, as illustrated
in Scheme 1c, we assumed that the treatment of 3-hydroxy-2-
(trialkylsilyl)phenyl triflate with a base would result in the
formation of the 3-(trialkylsiloxy)benzyne intermediate via a 1,3-
Brook rearrangement, which could further be used in
nucleophilic addition and cycloaddition. With these consid-
erations in mind, we now report the first documented use of 3-
hydroxy-2-(trialkylsilyl)phenyl triflate as a hydroxyaryne pre-
cursor induced via intramolecular anionic 1,3-silyl migration in
an aromatic system.
I
Scheme 1. Brook Rearrangement and Proposed Strategy for
Benzyne Formation
ment has been well-established and applied to various synthetic
transformations, including a multicomponent coupling.3 Specif-
ically, Smith and co-workers have employed the Brook
rearrangement for their multicomponent union tactic known as
anion relay chemistry (ARC).4
The reverse process, namely the migration of silicon from
oxygen to carbon, is known as the retro-Brook rearrangement
and is also frequently employed in organic chemistry (Scheme
1b).5 For instance, the reactions of trialkyl(2-bromophenoxy)-
silane with either lithium or sodium metal provide only o-
To demonstrate the proposed process for benzyne formation,
the requisite benzyne precursors 4 and 7 were prepared from 2-
bromoresorcinol 1 in three steps: O-silylation, lithium−halogen
exchange/triflation, and selective desilylation (Scheme 2).
Received: October 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
as Et2O, the desired product 9 was isolated in 40% yield after 12 h
(Table 1, entry 10). However, the use of a polar aprotic solvent
such as DME furnished 9 in 75% yield in 30 min (Table 1, entry
11). From these experiments, we conclude that the rate of silyl
group migration for the generation of the benzyne intermediate
depends on solvent polarity. As illustrated in entries 12 and 13, a
reduced temperature of −40 °C afforded the product 9 in a lower
yield of 15% after 12 h (Table 1, entry 12), while the yield
showed significant improvement when the reaction was
attempted at −20 °C (Table 1, entry 13). Finally, the use of 3
equiv of piperidine and 1.1 equiv of KOtBu in THF at room
temperature furnished 9 in 87% yield within 5 min (Table 1,
entry 14).
Scheme 2. Preparation of Benzyne Precursors 4 and 7
With the optimized conditions (cf. Table 1, entry 14) in hand,
we examined the scope of nucleophilic addition reactions
employing 3-hydroxy-2-TBS-phenyl triflate 4 and the various
nucleophiles (Scheme 3). Unfortunately, the use of our optimal
The reaction conditions for nucleophilic addition to benzyne
generated via 1,3-C-sp2-to-O silyl migration were initially
optimized by employing 3-hydroxy-2-TBS phenyl triflate 4 and
piperidine 8. As shown in Table 1, various bases, solvents, and
Scheme 3. Nucleophilic Addition Reactions Employing
Hydroxybenzyne Precursor 4
a
a
Table 1. Optimization Studies
b
entry
base
solvent
conditions
yield (%)
1
2
3
4
5
6
7
n-BuLi
NaHMDS
NaH
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
DME
THF
THF
THF
−78 °C, 1 min, 0 °C, 12 h
−78 °C, 1 min, 0 °C, 2 h
−78 °C, 1 min, 0 °C, 15 min
−78 °C, 1 min, 0 °C, 3 h
−78 °C, 1 min, 0 °C, 30 min
−78 °C, 1 min, 0 °C, 12 h
60 °C, 6 h
−78 °C, 1 min, 0 °C, 30 min
−78 °C, 1 min, 0 °C, 1 h
−78 °C, 1 min, 0 °C, 12 h
−78 °C, 1 min, 0 °C, 30 min
−40 °C, 12 h
67
75
80
62
83
0
KHMDS
KOtBu
MeMgCl
K2CO3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
82
78
69
40
75
15
57
87
c
8
d
9
10
11
12
13
14
−20 °C 12 h
rt, 5 min
a
Reaction conditions: 1 equiv of 3-hydroxy-2-TBS phenyl triflate, 3
b
equiv of piperidine, 1.1 equiv of base, solvent (0.1 M). Isolated yield.
c
d
2 equiv of piperidine. Piperidine was used as a limiting reagent.
temperatures were screened for the formation of the desired N-
arylated product 9. When 1.1 equiv of n-BuLi was used as a base
at 0 °C, the coupled product 9 was isolated in 67% yield after 12 h
(Table 1, entry 1). However, when the reactions were attempted
at 0 °C in the presence of either a sodium or potassium base such
as NaHMDS, NaH, KHMDS, or KOtBu, the benzyne
intermediate was generated within 3 h through a 1,3-Brook
rearrangement process, providing product 9 in yields ranging
from 62% to 83% (Table 1, entries 2−5). When MeMgCl was
employed as the base, no conversion was observed (Table 1,
entry 6). Interestingly, the use of K2CO3 as base in THF at 60 °C
furnished the desired product 9 in 82% yield in 6 h (Table 1,
entry 7). When the reaction was conducted with 2.0 equiv of 8, 9
was obtained in a slightly lower 78% yield in 30 min (Table 1,
entry 8). Furthermore, when 8 was employed as a limiting
reagent, 9 was obtained in 69% yield in 1 h (Table 1, entry 9).
Next, we investigated the solvent effects for N-arylation of
piperidine (Table 1, entries 10 and 11). As expected, when the
reaction was carried out using KOtBu in a nonpolar solvent such
a
Reaction conditions: 1 equiv of 3-hydroxy-2-TBS phenyl triflate, 3
b
c
equiv of nucleophile, THF (0.1 M). Desilylated product. 4 equiv of
KOtBu.
conditions proved not to be general for all substrates due to the
desilylation of the TBS group. Thus, we employed two different
sets of conditions to prevent the formation of the unwanted
desilylated product. As illustrated in Scheme 3, most of the
secondary amines (9a−c) and aromatic amines (9d−p)
containing electron-neutral, -donating, and -withdrawing groups
furnished the meta-selective N-arylated products in good to
excellent yields within 30 min. In particular, when the reaction
was conducted with 4-[(tert-butyldimethylsilyl)oxy]aniline, 9h
was obtained in 86% yield in 5 min. This result is especially
meaningful since it indicates that a substrate involving trialkylsilyl
B
DOI: 10.1021/acs.orglett.7b03160
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Organic Letters
Letter
protecting groups can serve as a nucleophile under the optimized
conditions. When ethyl 2-aminobenzoate was reacted with 3-
hydroxy-2-TBS phenyl triflate 4, the desired product 9k was
obtained in 80% yield along with a significant amount of 9kk.
Recently, Singh and co-workers reported the synthesis of N-aryl
sulfoximines using o-silylaryl triflates and sulfoximines in the
presence of a fluoride anion at room temperature.7c While they
demonstrated the possibility for N-arylation of sulfoximines
employing fluoride-activated aryne precursors, this reaction
afforded the desired products in 5% to 77% yields in 2−4 h. In
comparison, our method provided the product 9o in 82% yield in
15 min when methylphenylsulfoximine was employed. The
reaction was also successful with a heteroaryl amine such as 2-
aminopyrimidine as coupling partner, furnishing 9p in 74% yield
in 5 min. In addition, other nucleophiles such as thiophenol and
phenol proved to be effective coupling partners and afforded the
desired products 9q and 9r in 85% and 65% yields in 10 min,
respectively. Interestingly, the latter provided the undesired
homocoupled product 9rr in 12% yield, presumably due to the
competitive nucleophilic addition between the substrate and the
unreacted benzyne precursor 4.
Encouraged by these results, we next turned our attention to
the intermolecular [4 + 2], [3 + 2], and [2 + 2] cycloadditions
using benzyne precursor 4 and the corresponding arynophiles
(Scheme 5). Initially, when 3-hydroxy-2-TBS-phenyl triflate 4
Scheme 5. [4 + 2], [3 + 2], and [2 + 2] Benzyne
Cycloadditions
To further investigate the utility of a benzyne intermediate
induced via a 1,3-Brook rearrangement, a series of 3-hydroxy-2-
(trialkylsilyl)phenyl triflates 10 were employed as benzyne
precursors under two different sets of reaction conditions
(Scheme 4).8 Most of the reactions proceeded readily in 30 min
Scheme 4. N-Arylation Employing Various Hydroxybenzyne
a
Precursors 10 and Aniline 11
and 2,5-dimethylfuran 12 were treated with KOtBu at rt for 1 h in
THF, cycloadduct 13 was obtained in 35% yield along with a
significant amount of the homocoupled product 9rr in 20% yield.
However, when a weak base such as K2CO3 was employed at 60
°C in THF, the desired product was isolated in 72% yield in 8 h.
In the case of intermolecular [3 + 2] benzyne cycloaddition,
when either benzyl azide 14 or ethyl diazoacetate 16 was
employed, single regioisomers 15 and 17 were obtained in 46%
and 52% yield, respectively, in 12 h along with desilylated
products 15a and 17a in 21% and 11% yield. Furthermore, when
a mixture of 4 and 1,1-diethoxyethylene 18 was treated with
K2CO3 at 60 °C, a single regioisomer 19 was isolated in 80% yield
in 7 h.
From the outset of this work, it was hypothesized that the
benzyne intermediate from 4 could be induced by a 1,3-C-sp2-to-
O intramolecular silyl migration. With this in mind, we carried
out a crossover experiment wherein an equimolar mixture of 7
and 20 in the presence of aniline 11 was treated with 2.2 equiv of
KOtBu in THF (Scheme 6). No crossover products were
obtained in this reaction. This result indicates that silyl migration
occurs intramolecularly, presumably via a 1,4-cyclic, hypervalent
silicon intermediate and subsequent elimination of the triflate
group, affording the benzyne intermediate. To the best of our
knowledge, this is the first example of C-sp2-to-O 1,3-Brook
rearrangement in an aromatic system. Next, to investigate the
role of a fluoride anion in the presence of hydroxybenzyne
precursors, we repeated the reactions using triflate 4 and 11
under Larock’s conditions (Scheme 6b).7a To our surprise, the
desired product 9d was not isolated after 30 min, and desilylation
occurred to afford 21 in 80% yield; nonetheless, we found that
a
Reaction conditions: 1 equiv of hydroxybenzyne precursor, 3 equiv of
b
aniline, THF (0.1 M). Desilylated product.
to furnish the desired products in yields ranging from 68% to
91%. However, when 3-hydroxy-5-methoxy-2-TBS-phenyl tri-
flate was used, the coupled product 10d was obtained in 54%
yield in 40 min along with a significant amount of the desilylated
product 10dd in 20% yield. Interestingly, when either 3-hydroxy-
3-methyl-2-TBS-phenyl triflate or 3-hydroxy-6-methyl-2-TBS-
phenyl triflate was employed, the meta-selective products 10b
and 10c were obtained in 91% and 77% yield in 10 min,
presumably because of the steric and electronic effects resulting
from the tert-butyldimethylsilyloxy group of the aryne.
C
DOI: 10.1021/acs.orglett.7b03160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Author Contributions
Scheme 6. Preliminary Mechanistic Studies
∥Y.-J.K. and Y.-K.J. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) (NRF-2015R1A1A1A05001334) and the New &
Renewable Energy of the Korea Institute of Energy Technology
Evaluation and Planning (KETEP) grant (No.
20163030013900).
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03160.
Detailed experimental procedures and characterization
data (PDF)
(8) Various 3-hydroxy-2-TBS phenyl triflates were synthesized from 3
via C−H borylation, subsequent functionalization of the boryl group,
and selective desilylation (see the Supporting Information for details).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wonsukk@ewha.ac.kr.
ORCID
Won-Suk Kim: 0000-0001-9180-4570
D
DOI: 10.1021/acs.orglett.7b03160
Org. Lett. XXXX, XXX, XXX−XXX